Chronic HCV infection and associated liver disease are associated with impaired response to HBV/HAV vaccine and greater morbid outcomes upon pathogen exposure, yet strategies to improve these prophylactic vaccine responses are not available. Though effectiveness of HCV therapy will continue to improve, the substantial majority of HCV infected individuals remain untreated, and improving vaccine response will remain an important goal over the coming decade. Effects of HCV on the immune system that may contribute to impaired vaccine response include decreased naive CD4 cell and dendritic cell (DC) subset numbers, skewing of T-, B- and NK-cell subsets, and T cell exhaustion. Additionally, chronic HCV infection and associated liver disease are associated with immune activation (sCD14, LPS, IL-6, HLA-DR+CD38+CD4/8 cells). Emerging evidence, including our data, indicates HCV associated immune activation (CD16+56-NK subset frequency and sCD14) correlates with disease stage and negatively predicts host response to IFN therapy. To identify molecular drivers of immune activation we performed a non-biased comprehensive plasma proteome analysis to determine the correlates of immune activation. Our lead molecule was plasma ENPP2 (autotaxin). ENPP2 was elevated during HCV infection with advanced liver disease, and best correlated with CD4 activation during HCV infection. The product of ENPP2 activity, lysophosphatidic acid (LPA), activates T cells, providing a potential pathway amenable to therapeutic interruption. We propose HCV induced immune activation impairs host response to neoantigen (e.g. vaccine and new infectious challenge). Supporting this, during HIV infection where immune activation also exists, our preliminary data indicate higher CD4+HLADR+CD38+ T cell frequency negatively predicts host response to Hepatitis A vaccine, while greater naive CD4+ numbers positively predict response. Recent evidence also indicates markers of immune activation negatively predict HBV vaccine response during HCV infection. Older age is also associated with susceptibility to infection and impaired response to vaccine. The combined effects of aging and chronic HCV infection on the immune system are not yet characterized, but highly significant as this patient population continues to grow. Importantly, we observed that both aging and chronic HCV infection result in higher ENPP2 levels. Therefore ENPP2 may be a common therapeutic target, and an ideal metric in our proposed analyses. With the growing age of the US and VA HCV infected population, and with morbidity (cirrhosis, HCC, impaired therapy response) projected to peak in 2030 primarily in the aged HCV population, we propose that quantifying the combined effects of age and chronic HCV infection on the immune system, and the impact of ENPP2 on the neoantigen response will guide therapeutic strategies. In Aim 1 we will Determine the independent contributions of untreated HCV, immune activation, age, ENPP2 and LPA to neoantigen (hepatitis A/B vaccine) vs. recall antigen (tetanus booster vaccine) response. In Aim 2 we will Determine the effect of ENPP2 inhibition on murine host response to neoantigen in the setting of chronic LCMV infection.